ICU · pharmacology

ICU Antibiotic Pharmacology — Comprehensive (PK/PD in Critical Illness)

Also known as Antibiotic dosing in ICU · PK/PD critical illness · Augmented renal clearance · Beta-lactam continuous infusion · DALI study · BLING trial · Vancomycin AUC monitoring · Therapeutic drug monitoring antibiotics · Beta-lactam fT>MIC · Aminoglycoside once-daily dosing

ICU antibiotic pharmacology — the evidence-based framework for optimising antimicrobial dosing in critically ill patients where altered pharmacokinetics (PK) make standard doses unreliable. Core problem: critical illness DISRUPTS PK in predictable directions — (1) INCREASED VOLUME OF DISTRIBUTION (Vd) from capillary leak and aggressive fluid resuscitation → LOWER plasma concentrations of hydrophilic drugs (beta-lactams, aminoglycosides, glycopeptides) → need HIGHER loading doses; (2) AUGMENTED RENAL CLEARANCE (ARC — measured CrCl 130 mL/min) in young trauma/burns/sepsis/neuro-injury patients → enhanced renal elimination → subtherapeutic levels → need HIGHER and/or MORE FREQUENT doses (especially beta-lactams and vancomycin); (3) renal replacement therapy (RRT/CRRT) clears renally-eliminated drugs → need supplemental dosing; (4) HYPOALBUMINAEMIA → increased free (active) drug fraction → variable effect (more free drug but also more Vd for highly protein-bound drugs like flucloxacillin, teicoplanin, daptomycin). Pharmacodynamic (PD) targets determine HOW to dose: BETA-LACTAMS = time above MIC (fTMIC — achieve 100% fTMIC, ideally 100% fT4xMIC, via CONTINUOUS or EXTENDED [prolonged 3-4h] infusion); AMINOGLYCODSIES = Cmax/MIC ratio (concentration-dependent killing + post-antibiotic effect → high peak ONCE DAILY, target gentamicin Cmax 8-12 mg/L); FLUOROQUINOLONES = AUC/MIC ratio (target AUC/MIC 125 for Gram-negatives); VANCOMYCIN = AUC/MIC 400-600 (2020 consensus shifted from trough 15-20 mg/L to AUC-guided Bayesian monitoring — AUC24 400-600 mg·h/L). Key DALI study finding: with STANDARD beta-lactam dosing, ~75% of ICU patients FAILED to achieve 50% fTMIC target → underdosing is the rule, not the exception → paradigm shift to PERSONALISED dosing + therapeutic drug monitoring (TDM). Key antibiotic classes: beta-lactams (PIP-TAZO, cefepime, meropenem [ESBL], ceftriaxone [CAP — NO Pseudomonas cover]), glycopeptides (vancomycin [MRSA, enterococcus — TDM], teicoplanin), aminoglycosides (gentamicin [once daily — TDM — nephrotoxicity + ototoxicity]), fluoroquinolones (ciprofloxacin [Pseudomonas], moxifloxacin [CAP — no Pseudomonas]), macrolides (azithromycin [CAP — atypicals]), oxazolidinones (linezolid [VRE, MRSA — thrombocytopenia, serotonin syndrome with SSRIs]), antifungals (caspofungin [Candida], voriconazole [Aspergillus], liposomal amphotericin B [broad — nephrotoxic]).